Summary | Heart failure & Diabetes: Time for a more unified approach

In management of HF, it is most important to consider comorbidities in HF, and to individualize therapy by patients’ comorbidities. Diabetes is one of many comorbidities in chronic (C)HF, and associated with a 9-fold increase in mortality for patients with both diabetes and HF compared to those with diabetes alone.18 In the past, HbA1c-guidance was considered as an approach to treat HF patients. Epidemiology studies have, however, described several different shapes of relationships, thus discrediting HbA1c as a suitable marker to guide treatment of HF patients. In CHF trials, about 20-40% of patients had T2DM.

Because most patients in the EMPA-REG OUTCOME trial did not have HF at baseline, the data suggest that empagliflozin may prevent development of HF.

A number of trials have targeted patients with CVD including HF, but did not specifically focus on HF patients. Nevertheless, we can learn about the treatment of HF patients from these trials, such as the EMPA-REG OUTCOME trial.19 The SGLT2 inhibitor empagliflozin reduced glucose by renal excretion, resulted in loss of calories, body weight, and fluid, and BP was decreased, which are all beneficial effects for HF patients.20 Patients had to have established CVD, but HF was a not a qualifying criterium for this study. Patients with HF in the trial (about 700) were older, had a higher percentage from Europe and a higher BMI compared to patients without HF. Other than CVD, it is possible that patients with HF were included at baseline. Unfortunately, EF, NYHA class or the BNP value are not known. Many of them had kidney dysfunction with GFR <60. Interestingly, the EMPA-REG OUTCOME trial had 3-point MACE as primary outcome and secondary endpoints included hospitalization for HF as an important prospectively specified endpoint. In patients on empagliflozin, all-cause and CV mortality decreased, as did hospitalization for HF. Because most patients did not have HF at baseline, the data suggest that empagliflozin may prevent development of HF. Statements about treatment of existing HF are difficult to make, because it is not known who had HF at baseline. However, comparing the 700 HF patients with the rest of the patient population showed similar results for empagliflozin, regardless of type of outcome event, indicating that these HF patients with T2DM benefitted equally as those without HF.

To get an idea what kind of HF patients these were, Anker compared event rates in the EMPA-REG OUTCOME trial with those in several HF trials. Event rates in the overall EMPA-REG OUTCOME trial showed 15 hospitalization per 1000 patient years of follow-up, but in the subgroup of patients with HF this was 52. This is about in the middle of what has been observed in HFpEF trials. The CHARM trial in patients with systolic HF reported ~1 in 10 deaths for all-cause mortality per 1000 patient years of follow-up. HFpEF trials showed about half that mortality rate, as did the EMPA-REG OUTCOME trial with 55 events per 1000 patient years. Anker concludes that this suggests that the EMPA-REG OUTCOME trial may have consisted of a HFpEF patient population. Thus, he thinks that these results indicate that empagliflozin may be used to treat HFpEF patients, although this was not a prespecified idea in the trial. In addition, EF and precise details are not known. The guidelines for CHF patients with diabetes recommend using standard HF medication (ACE-I, ARB, -blockers) or metformin (level IIa with level of evidence C (expert consensus) recommendation) and glitazones should not be used. For the prevention of development of HF, empagliflozin should be considered, but it has a IIa indication with level of evidence B (based on 1 trial).21

Considering treatment of HF, the results of the EMPA-REG OUTCOME trial should be cautiously interpreted, as other trials have shown to misguide us in the past. For example the trials on vesnarinone; a small trial first showed surprisingly positive results, which could not be confirmed in a larger trial.22,23 In addition, we cannot conclude anything on prediabetes in HF patients. About 20-50% of HF patients have prediabetes, but these patients have not been included in trials.

To answer these outstanding questions, new trials have been designed. The use of empagliflozin in patients with HF with reduced EF will be tested in the EMPEROR-Reduced trial with a total of 3000 patients, and later it will be tested in patients with HFpEF in EMPEROR-Preserved (4100 patients). Treatment with dapagliflozin is tested in a HFpEF population in the DAPA-HF trial enrolling 4500 patients. The difference between these trials is the BNP inclusion criterium. In all these trials, CV death and HF hospitalization are the primary endpoints.

These trials are essential, because no data on SGLT2 inhibitors are available in the treatment of HF patients, and it is necessary to validate the results of the EMPA-REG OUTCOME trial. It is unknown whether the benefits demonstrated in the EMPA-REG OUTCOME study population will extend to a true HF population. For instance, the CORONA and GISSI-HF programs have demonstrated that statins did not yield benefit for HF patients, unlike in patients with CVD. In addition, it is not clear which type of HF patients were included in EMPA-REG-OUTCOME (HFrEF, HFpEF, HFmrEF). Thus, we need to better understand in which patients these drugs are most beneficial.

References

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